The neurobiological mechanisms that underlie the transition from controlled to uncontrolled, or excessive, drinking are not completely understood. Excessive drinking has been demonstrated following several different ethanol exposure paradigms in monkeys, rats and mice. Furthermore, the initiation and maintenance of ethanol self-administration involves several brain regions including the nucleus accumbens, amygdala and hippocampus. In addition, specific neurotransmitter receptor subtypes and/or transporters within these brain regions have been implicated in excessive ethanol self-administration. Recently, it has been demonstrated that acute stress administration can result in high levels of ethanol self-administration and reinstatement of ethanol self-administration in drug free animals. However, it is currently unknown if the initiation of excessive drinking is influenced by interactions between stress, specific brain regions, and specific genes. The current proposal will 1) investigate the neurobiological relationship between stress, anxiety and excessive drinking in knockout mice; 2) investigate the neurobiological relationship between chronic ethanol administration, stress and ethanol self-administration in knockout mice; and 3) identify significant neurobiological abnormalities in the relationship between stress and acute ethanol administration in knockout mice. These studies will fill a major gap in understanding the relationship between stress, brain regions, genetics and the development of excessive drinking.